Prostaglandin D2 (PGD2), a metabolite derived from arachidonic acid through PGG2 and PGH2, is known to have a variety of potent biological activities. For example, PGD2 is involved in biological actions such as sleep induction and hormone secretion in the central nervous system, inhibition of platelet aggregation, contraction of airway smooth muscle, and relaxation or constriction of vascular smooth muscle in the peripheral tissue (Pharmacol. Rev. (1994) 46, 205-229). In addition, PGD2 is the major metabolite of arachidonic acid produced by mast cells and can cause strong bronchoconstriction, increased vascular permeability, and migration of inflammatory cells such as eosinophils. From these findings, PGD2 is considered to be deeply involved in the pathogenesis in allergic diseases such as asthma.
Formerly, only DP receptor is known as a PGD2 receptor and antagonists against its receptor are described in WO 98/25915, WO 01/66520, WO 01/79169 and the like.
However, it was suggested that there would be other PGD2 receptors different from DP receptor because BW-245C which is a selective agonist against DP receptor did not have activity for eosinphil infiltration (J. Immunol. (1992) 148, 3536-3542; Invest. Ophthalmol. Vis. Sci. (1990) 31, 138-146; Br. J. Pharmacol. (1985) 85, 367-375; J. Pharmacol. Exp. Ther. (1995) 275, 611-617 etc.). Recently, it was reported that CRTH2 receptor is the other PGD2 receptor and PGD2 causes wandering of eosinophils and basophils vir this receptor (J. Exp. Med. (2001) 193, 255-261).
An antagonist against thromboxane A2 (TXA2) receptor and a platelet aggregation inhibitor having similar structure to a compound of the present invention are described in JP-A-61-249960, JP-A-62-198659, JP-A-62-249969, JP-A-2-193965, JP-A-3-151360, JP-A-4-230363, JP-A-4-234846, JP-A-4-257578, JP-A-8-157471, JP-A-8-245587, DE 3909600, Eur. J. Med. Chem., (1991) 26(8), 821-827. However, PGD2 antagonistic activity of the above compounds has not been described in them.
It is described in JP-A-3-151360 that 3-(4-chlorophenylsulfonylamino)-9-(2-carboxymethyl)-1,2,3,4-tetrahydrocarbazole and its ethyl ester have TXA2 antagonistic activity and TXA2 synthetase inhibitory activity. However, concrete value of the activities is not described in the document.
It is described in Eur. J. Med. Chem., 1991, 26(8), 821-827 that 3-(4-chlorophenylsulfonylaminoehtyl)indole-1-acetic acid and 3-(4-chlorophenylsulfonylaminopropyl)indole-1-acetic acid have antagonistic activity against TXA2/PGH2 receptor.
It is described that 3-(4-fluorophenylsulfonamide)-1,2,3,4-tetrahydro-9-carbazole propionic acid is useful for therapeutic agent for allergic dermatitis, allergic dermatitis vir delayed type allergy reaction, and psoriasis in JP-A-7-175991, WO 97/44031, JP-A-11-106337 and JP-A-11-116477. It is described in JP-A-11-322600 that the above compound has depression activity for Chemokine production. Further, it is described in J. Allergy Clin. Immunol. (1992) 89, 1119-1126 that there is possibility that the above compound will have PGD2 antagonistic activity via DP receptor because it shows a depression effect against bronchus constriction caused PGD2. However, according to 1) PGD2 also binds TXA2 receptor in high concentration range (more than 1 μM) (Eur. J. Pharmacol. (1992) 226, 149-156; Br. J. Pharmacol. (1991) 103, 1883-1888 etc., 2) antagonists against TXA2 receptor which have weak receptor affinity for DP receptor show the same depression effect (Int. Arch. Allergy Immunol. 1992, 98, 239-246, and 3) selective DP receptor antagonists does not show a depression effect against bronchus constriction caused PGD2 (Br. J. Pharmacol. (1989) 96, 291-300), it is known time that the above depression effect is caused by depressing the reaction via thromboxane receptor and the above compound does not have direct DP receptor antagonistic activity at the present.
It is described in EP 1170594 that 4 compounds selectively binds CRTH2 receptor in comparison with DP receptor. However, the structures of the compounds are not similar to the compound of the present invention and details such as binding activities are not described.